There are an estimated 250,000-400,000 sudden cardiac deaths (SCD) annually in the United States constituting approximately 50% of all cardiac deaths. Although clinical trials have demonstrated convincing survival benefits conferred by implantable cardioverter defibrillator (ICD) therapy in selected patients with left ventricular ejection fractions (LVEF) less than 35% and congestive heart failure, the overwhelming majority of patients who suffer a cardiac arrest will have an LVEF>0.35. This grant application, "PRE-DETERMINE: Biologic Markers and MRI SCD Cohort Study," seeks to identify patients at a substantially higher risk of arrhythmic death among CHD patients with preserved left ventricular ejection fractions (LVEF>35%). The application takes advantage of a planned randomized trial, the Defibrillators To Reduce Risk by Magnetic Resonance Imaging Evaluation (DETERMINE) trial sponsored by St. Jude Medical to assemble a unique prospective cohort of patients who do not presently have an indication for ICD therapy based upon left ventricular function. The additional support from the NHLBI will provide a unique and timely opportunity to take advantage of the assembly of patients screened for the trial who will have contrast-enhanced magnetic resonance imaging (CE-MRI) scans to create an invaluable cohort of 5300 patients with preserved LVEFs where the underlying cardiac substrate is well-defined by MRI imaging and where clinical information, lifestyle habits, electrocardiograms, and blood samples will be collected at baseline and sudden arrhythmic events will be documented over the follow-up period. In years 4-5, the predictive value of promising protein, genetic, and metabolic biomarkers in combination with advanced substrate imaging on the risk of arrhythmic events will be examined in the 6850 patients enrolled in both the observational PRE-DETERMINE cohort and in the parent DETERMINE randomized trial. The goal is to arrive at a series of markers that alone or in combination specifically predict risk of arrhythmic death as compared to other causes of mortality among this at risk population of CHD patients. If biomarkers or genetic markers are identified that can specifically predict risk of ventricular arrhythmias, then these markers may serve as relatively inexpensive methods to identify those at risk. PUBLIC HEALTH RELEVANCE: The public health impact of identifying markers could be quite substantial, leading to more efficient utilization of ICDs and advances in our understanding of mechanisms underlying SCD. The goal of this application is to improve our ability to identify patients who will die suddenly from coronary heart disease through the study of genes and blood markers. If these markers can predict risk of dying suddenly, then they may serve as relatively inexpensive methods to identify those patients at risk. The public health impact of identifying such markers could be quite substantial, leading to more efficient utilization of implantable cardioverter defibrillators and advances in our understanding of mechanisms underlying life-threatening rhythm disturbances.